The cholinergic deficit is the strongest neurochemical correlate of the severity of dementia in patients with Alzheimer's disease (AD). Several post-mortem studies of patients with AD have demonstrated the loss of the 1422-subtype of the nicotinic acetylcholine receptor (1422-nAChR) in the cerebral cortex, hippocampus and striatum, brain regions with a moderate density of 1422-nAChRs, but not in thalamus, a region with the highest density of 1422-nAChRs. In vivo imaging studies of extrathalamic 1422-nAChRs (ETNRs) have been limited by the availability of suitable positron emission tomography (PET) radioligands. The overall objective of this proposal is to develop a radioligand for quantitative PET imaging of ETNR in human subjects that will make it possible to investigate the nicotinic system in neurodegenerative disorders, especially AD. Currently, only one radioligand, 2-[18F]FA, is available for PET imaging of thalamic 1422-nAChRs and its properties for imaging of ETNRs are poor. R21: [18F]XTRA, the first radioligand with properties suitable for quantitative PET imaging of the ETNRs in animals, was recently developed by our group. In the R21 phase (Year 1) we will perform pre-clinical studies with [18F]XTRA that include (1) efficient synthesis of precursor for radiolabeling of [18F]XTRA;(2) in vivo pharmacology and radiation dosimetry studies in mice;and (3) baseline and blocking experiments in baboons using PET. By the end of the R21 phase we will file an exploratory IND for human studies with [18F]XTRA. R33: In the R33 phase (Years 2-4) and after FDA approval of the eIND, [18F]XTRA, will be quantified for pharmacokinetics, distribution density, binding potential and total distribution volume of the ETNRs in the brain of young human control subjects (18-45 years old). Appropriate PET models for quantification of ETNRs with [18F]XTRA in human brain will be developed. Radiation dosimetry of [18F]XTRA in humans will be also obtained in Year 2 to assure the safety of [18F]XTRA for two or more PET scans per subject, enabling human test/re-test PET scans in Year 2. PET experiments in elderly human control subjects (over age 60) will be performed in Year 3. The results of those experiments will be compared with PET scans of age-matched patients with AD (over age 60) (Year 4). Significant differences are expected in [18F]XTRA binding in the extrathalamic regions (frontal and temporal cortices, hippocampus and striatum) in young subjects compared to elderly people and in patients with AD compared to age-matched controls. Our long term goals are to evaluate 1422-nAChR as a biomarker of AD by studying the longitudinal course of receptor changes in AD and mild cognitive impairment and to test the sensitivity of these receptors the effects of cholinergic treatment. PUBLIC HEALTH RELEVANCE: Development of radioligands for positron emission tomography (PET) imaging of the extrathalamic nicotinic receptors (ET 1422-nAChR) is of great importance for studying the role of the nicotinic system in neurodegenerative disorders, schizophrenia, drug dependence and a variety of other disorders as well as for developing nicotinic medications to treat these conditions.